title: Lymphatic absorption, metabolism, and excretion of a therapeutic peptide in dogs and rats.
abstract: The objective of the current study was to evaluate the mechanism of absorption and metabolism of a PEGylated peptide, MRL-1 (46 kDa), after s.c. dosing in dogs and rats. Thoracic lymph duct-cannulated (LDC) dog and rat models were developed that allowed continuous collection of lymph for up to 8 days. When [(3)H]MRL-1 was administered s.c. to LDC dogs, ∼73% of the administered radioactivity was recovered in pooled lymph over a period of 120 hours, suggesting that lymphatic uptake is the major pathway of s.c. absorption for this peptide. In agreement with these data, the systemic exposure of radioactivity related to [(3)H]MRL-1 in LDC dogs was decreased proportionately when compared with that in noncannulated control dogs. After i.v. dosing with [(3)H]MRL-1 in LDC dogs, 20% of the administered radioactivity was recovered in pooled lymph over 168 hours, suggesting some level of recirculation of radioactivity related to [(3)H]MRL-1 from the plasma compartment into the lymphatic system. Experiments conducted in the LDC rat model also resulted in similar conclusions. Analysis of injection site s.c. tissue showed significant metabolism of [(3)H]MRL-1, which provides an explanation for the <100% bioavailability of therapeutic proteins and peptides after s.c. dosing. After s.c. dosing, the major circulating components in plasma were the parent peptide and the PEG-linker [(3)H]MRL-2. The metabolism profiles in lymph were similar to those in plasma, suggesting that the loss of peptide was minimal during lymphatic transport. After i.v. dosing in rats, [(3)H]MRL-1 was metabolized and excreted primarily in the urine as metabolites.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (Y.Z., T.J.B., V.B.G.R.), Safety Assessment and Laboratory Animal Resources (C.A., X.S., P.K.C., B.W., T.T., A.C., X.H., C.N.N., C.V.J.), and Labeled Compound Synthesis (A.S.Z., S.J.S.), Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bateman
authors.forename: Christine
authors.initials: C
authors.lastname: Adreani
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Shen
authors.forename: Paul K
authors.initials: PK
authors.lastname: Cunningham
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Tu
authors.initials: T
authors.lastname: Trinh
authors.forename: Amy
authors.initials: A
authors.lastname: Christine
authors.forename: Xuening
authors.initials: X
authors.lastname: Hong
authors.forename: Christian N
authors.initials: CN
authors.lastname: Nunes
authors.forename: Chris V
authors.initials: CV
authors.lastname: Johnson
authors.forename: Andy S
authors.initials: AS
authors.lastname: Zhang
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Staskiewicz
authors.forename: Matthew
authors.initials: M
authors.lastname: Braun
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Vijay Bhasker G
authors.initials: VB
authors.lastname: Reddy
mesh_terms: D000042:Absorption; D000279:Administration, Cutaneous; D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D001578:Benzopyrans / Q000378:metabolism*; D001682:Biological Availability; D001692:Biological Transport / Q000502:physiology; D004285:Dogs; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C499784:7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid; D001578:Benzopyrans